Abstract Project 2 takes an integrated, molecular approach to understanding modifiable factors for colorectal cancer (CRC) risk and survival. A number of factors (metabolism, energy balance, aspirin, vitamin D) have been associated with CRC risk, and substantial intersections exist between nutrient excess, derangements in cellular and molecular mediators of inflammation, and vitamin D insufficiency, which jointly appear to drive CRC development and progression. Nonetheless, there remains a critical need to further investigate these interventions before clinical translation. We will leverage the resources of 3 unique and rich study populations to pursue innovative conceptual and technical approaches, which have not been or only rarely used to date to study CRC. Specifically, using two large cohorts of women (NHS) and men (HPFS) with >35 years of follow- up, we will examine underlying mechanistic pathways by incorporating metabolomic profiles, tumoral gene expression and whole exome sequencing data to understand and further define strategies for improving CRC prevention and treatment. Beyond our hypothesis-based work, we will further leverage these innovative and novel platforms to systemically identify new targets for prevention and therapy. Moreover, building on our extensive published observational work in these cohorts assessing the role of vitamin D in colorectal carcinogenesis, we will now examine the influence of vitamin D supplementation on risk of colorectal adenoma within a large, placebo-controlled randomized clinical trial (RCT; the VITAL study), which oversampled for African-Americans due to their higher prevalence of vitamin D deficiency. Finally, among NHS and HPFS participants diagnosed with CRC, we will examine the relation of these modifiable factors to survival following CRC treatment. We are uniquely positioned to address these critical research questions in these well- established study cohorts with long-term follow-up, archived blood and tissue specimens, a validated metabolomics platform, and the ability to evaluate post-diagnostic exposures while controlling for pre- diagnostic behaviors. Findings from this novel, comprehensive investigation will substantially enhance our understanding of CRC etiology, its molecular subtypes, and survival. Identifying modifiable factors to improve CRC survival has potential translational implications through changes in clinical recommendations. Together with Projects 1, 3, and 4, our aims also will identify etiology and prevention for 3 of the top 5 causes of cancer death.